Hydrolysis of acylamino acids

ABSTRACT

A process for the preparation of racemic amino acids, characterized in that an acylamino acid of the formula 
     R 1 —CH(NH—CO—R 2 )COOH 
     wherein R 1  is hydrogen, a linear, branched or cyclic alkyl that has from 1 to 7 carbon atoms and that may contain substituents such as a hydroxyl, alkyloxy or alkylthio group; and R 2  is a hydrogen atom or an alkyl having from 1 to 3 carbon atoms; is heated in the presence of water, in a pressure-resistant vessel, to a temperature in the range from 110° C. to 220° C. and is hydrolyzed

INTRODUCTION AND BACKGROUND

[0001] The present invention relates to a process for the preparation ofamino acids, particularly by hydrolysis of acylamino acids.

[0002] Amino acids are used in human medicine and in the pharmaceuticalsindustry, in the foodstuffs industry and, very particularly, in thefeeding of animals. Amino acids can be in enantiomerically pure form,but also in the form of the racemate. Amino acids are also used in thesynthesis of numerous fine chemicals and active ingredients.

[0003] Various processes are available for the industrial production ofamino acids, such as the hydrolysis of proteins, the Strecker process,biotechnological processes and amido-carbonylation.

[0004] The reaction known as amidocarbonylation is the conversion ofcarbonyl compounds or alkenes with acylamides as the nitrogen source andcarbon dioxide or synthesis gas. The first products of that reaction arenot the free amino acids, but the N-acylamino acids. Such N-acylaminoacids are valuable starting materials for the enzymatic racematecleavage for the preparation of enantiomerically pure amino acids(Beller et al., Chem. Eur. J. 1998. 4, 935-941).

[0005] It is, however, not important to use an enantiomerically pureform in all applications of amino acids. There is also a need forracemic amino acids. An example thereof is D,L-methionine, a racemicamino acid, which is used in large amounts as a feed additive foranimals and poultry.

[0006] The hydrolysis of acylamino acids to amino acids is usuallycarried out by reaction with aqueous lye or mineral acid in at leastequimolar amounts. Examples thereof are given, for example, in anarticle by J. F. Knifton (Catalysis Today, 18 (1993) 355-384). In orderto isolate the amino acid, the lye or mineral acid that has been addedmust then be neutralized once the reaction is complete. Owing to the insome cases good solubility of amino acids and the salts in water formedon neutralization, the separation from the salt on isolation of the pureamino acids is often associated with considerable expense and losses.When ion exchangers are used, salt formation is not avoided but simplymoved to a different process stage. The large amount of salt that isinevitably formed in that process is highly disadvantageous for anindustrial application from an ecological and an economic point of view.

[0007] It is also known that amides can be hydrolyzed with water in theregion of the critical point (374° C., 218 atm) without the addition ofacids or lyes. Under such conditions, however, the technicalrequirements are considerable. The reaction medium is highly corrosivein that temperature range and high-quality materials are thereforerequired for the construction of reaction equipment.

[0008] In consideration of the prior art outlined and discussed above,it is an object of the present invention to find a further process forthe preparation of racemic amino acids from acylamino acids, in whichthe amino acids can readily be isolated and the formation of largeamounts of salts is avoided.

SUMMARY OF THE INVENTION

[0009] The above and other objects of the present invention can beachieved by a process for the preparation of racemic amino acids,wherein an acylamino acid of the general formula

R¹—CH(NH—CO—R²)COOH

[0010] wherein

[0011] R¹ is hydrogen, linear, branched or cyclic alkyl that has from 1to 7 carbon atoms and that may contain substituents such as a hydroxyl,alkyloxy or alkylthio group; and

[0012] R² is a hydrogen atom or an alkyl having from 1 to 3 carbonatoms;

[0013] is heated in the presence of water, in a pressure-resistantvessel, to a temperature in the range from 110° C. to 220° C. and ishydrolyzed.

[0014] It has been found that acylamino acids can also be hydrolyzed ina temperature range that is markedly below the critical temperaturewithout the addition of acids or bases.

DETAILED DESCRIPTION OF THE INVENTION

[0015] An important aspect according to the present invention is thatthe required temperature range that is necessary in the processaccording to the invention is markedly below the critical temperature,which means that the demands made of the materials and the requiredpressure resistance of the reaction vessel lie within normal limits.

[0016] In particular and surprisingly, it has now been found that theprocess according to the invention may preferably be carried out in sucha manner that the desired racemic amino acids can be prepared withoutthe aid of further substances and can then be obtained from the aqueousreaction solution with purities of >95% with, at the same time, a veryhigh degree of selectivity.

[0017] In a preferred embodiment of the process of the invention, thehydrolysis is carried out at temperatures from 110° C. to 220° C.,preferably from 140° C. to 200° C., particularly preferably from 140° C.to 180° C.

[0018] Racemic amino acids prepared in that manner are of high purityand can be used for many applications without further purification.

[0019] Suitable acylamino acids are compounds of the general formulaR¹—CH(NH—CO—R²)COOH wherein R¹ is hydrogen, a linear, branched or cyclicalkyl that has from 1 to 7 carbon atoms and that may containsubstituents such as a hydroxyl, alkyloxy or alkylthio group. R²represents a hydrogen atom or an alkyl having from 1 to 3 carbon atoms.

[0020] Examples of linear, branched or cyclic alkyls are methyl, ethyl,propyl, isopropyl, 1-methylpropyl, 2-methylpropyl, butyl and cyclohexyl,with alkyls having from 1 to 5 carbons being preferred. Such alkyls maybe substituted by from 1 to 3 amino, hydroxyl, halogen, alkyloxy,alkylthio, urea or carboxy groups.

[0021] According to the invention, the acylamino acid to be hydrolyzedis heated together with water in a pressure-resistant vessel. Thepressure that builds up corresponds to the vapor pressure of the waterat the corresponding temperature.

[0022] The hydrolysis may be carried out continuously ordiscontinuously.

[0023] The amount of water required is dependent on the nature of theacylamino acid and is generally in a range from 0.3 to 2.0 liters (l),preferably from 0.5 to 1.5 l/mol of acylamino acid. The reaction timerequired for complete conversion is affected by the amount of water, anincrease in the amount of water shortens the reaction time. It is alsoadvantageous during the reaction to remove from the equilibrium bydistillation the carboxylic acid that forms, or a portion thereof.However, it is also possible to separate off the carboxylic acid oncethe reaction is complete.

[0024] When the reaction is complete, the reaction solution contains, inaddition to small residual amounts of the acylamino acid that was used,the amino acid that has formed, the carboxylic acid analogous to theacyl group used, and traces of condensation products. Isolation of theamino acid from the reaction solution may be effected by various methodsknown per se, the method depending on the solubility of the amino acidand the properties of the carboxylic acid. Before or after separation ofthe amino acid, or of a portion thereof, in the form of a crystallisate,the carboxylic acid is largely separated off by distillation, azeotropicdistillation or extraction. Ketones, such as methyl isobutyl ketone, orethers, such as methyl tert-butyl ether, may be used as the extractingagent.

[0025] For separation of the amino acid in the form of a crystallisate,the solution, particularly in the case of readily soluble amino acids,may be concentrated. The filtrate obtained after separation of thesolids is a saturated aqueous solution of the amino acid and may be usedin the hydrolysis again together with fresh acylamino acid.

[0026] The Examples which follow are intended to illustrate theinvention, without having a limiting effect.

EXAMPLE 1

[0027] A mixture of 19.1 grams (g) of N-acetyl-D,L-methionine and 150milliliters (ml) of water was heated for 1 hour at 180° C. in alaboratory autoclave. After cooling to room temperature, 6.1 g ofcrystalline methionine (content, determined by HPLC: 99.7%) wereobtained. A further 5.9 g of methionine and 3.4 g of acetyl-methioninewere contained in the filtrate. The conversion of the acetyl compoundwas 82.2%, the selectivity of the reaction was 97.8%.

EXAMPLE 2

[0028] A metering pump was attached to a laboratory autoclave having avolume of 250 ml, and a condenser was attached downstream of a valve.The autoclave was filled with 20 g of acetylmethionine and 150 ml ofwater and heated to 160° C., with stirring. At 20-minute intervals, thevalve was opened slightly until in each case 20 ml of condensationproduct of water and acetic acid were obtained. The level in theautoclave was kept constant by pumping in the same volume of water. Theinternal temperature was in the range from 140° C. to 160° C. for 4hours. After cooling to 20° C., 8.2 g of pure methionine were filteredoff. The filtrate contained a further 5.1 g of methionine and 2.7 g ofacetyl-methionine. The conversion was 86.5%, the yield was 85.1%, whichcorresponded to a selectivity of 98.3%.

EXAMPLE 3

[0029] A mixture of 15.9 g of N-acetyl-D,L-valine and 150 ml of waterwas heated for 2 hours at 180° C. in an autoclave having a volume of 250ml. Subsequent analysis (HPLC) showed, at a conversion of 84.7%, a yieldof 83.5%, which corresponded to a selectivity of 98.5%.

[0030] Further variations and modifications of the foregoing will beapparent to those skilled in the art and are intended to be encompassedby the claims appended hereto.

[0031] German application 100 39 268.7 is relied on and incorporatedherein by reference.

We claim:
 1. A process for the preparation of a racemic amino acid,comprising heating in the presence of water in a hydrolysis reaction ofan acylamino acid of the formula R¹—CH(NH—CO—R²)COOH wherein R¹ ishydrogen, a linear, branched or cyclic alkyl that has from 1 to 7 carbonatoms optionally substituted with a hydroxyl, alkyloxy or alkylthiogroup; and R² represents a hydrogen atom or an alkyl having from 1 to 3carbon atoms; in a pressure-resistant vessel, to a temperature in therange from 110° C. to 220° C. and hydrolyzing said acylamino acid in thehydrolysis reaction to obtain said racemic amino acid.
 2. The processaccording to claim 1, wherein the hydrolyzing is carried out in atemperature range from 140° C. to 200° C.
 3. The process according toclaim 2, wherein the hydrolyzing is carried out in a temperature rangefrom 140° C. to 180° C.
 4. The process according to claim 1, wherein acarboxylic acid is formed in the hydrolysis reaction, and furthercomprising removing at least a portion of said carboxylic acid from thereaction solution during the reaction or after the reaction is complete.5. The process according to claim 2, wherein a carboxylic acid is formedin the hydrolysis reaction, and further comprising removing at least aportion of said carboxylic acid from the reaction solution during thereaction or after the reaction is complete.
 6. The process according toclaim 3, wherein a carboxylic acid is formed in the hydrolysis reaction,and further comprising removing at least a portion of said carboxylicacid from the reaction solution during the reaction or after thereaction is complete.
 7. The process according to claim 1, wherein afterthe reaction is complete, separating off the amino acid in the form of asolid.
 8. The process according to claim 2, wherein, after the reactionis complete, separating off the amino acid in the form of a solid. 9.The process according to claim 3, wherein, after the reaction iscomplete, separating off the amino acid in the form of a solid.
 10. Theprocess according to claim 7 further comprising recycling filtrateobtained in separating off the amino acid.
 11. A process for thepreparation of a high purity racemic amino acid, comprising reacting anacylamino acid of the formula R¹—CH (NH—CO—R²)COOH wherein R¹ ishydrogen, a linear, branched or cyclic alkyl that has from 1 to 7 carbonatoms optionally substituted; and R² represents a hydrogen atom or analkyl having from 1 to 3 carbon atoms; in a hydrolysis reaction byheating in the presence of water, in the range of 0.3 to 2 liters ofwater per mol of acylamino acid, to a temperature in the range from 110°to 220° and thereby hydrolyzing the resulting reaction solutioncontaining acylamino acid.
 12. The process according to claim 11,wherein the hydrolysis is carried out in a temperature range from 140°C. to 200° C.
 13. The process according to claim 12, wherein thehydrolysis is carried out in a temperature range from 140° C. to 180° C.14. The process according to claim 11, wherein carboxylic acid formed inthe hydrolysis reaction is at least partially removed from the reactionsolution during the reacting or after reacting is completed.
 15. Theprocess according to claim 11, after the reacting is complete, aminoacid formed is separated off in the form of a solid, and filtrate isrecycled.
 16. A process for the production of methionine by hydrolysiscomprising forming a reaction solution of acetyl methionine in water,heating said reaction solution in a pressure-resistant vessel, to atemperature in the range from 110° C. to 220° C. for a sufficient periodof time to achieve hydrolysis to obtain said methionine.
 17. The processaccording to claim 16, wherein the hydrolysis is carried out in atemperature range from 140° C. to 200° C.
 18. The process according toclaim 17, wherein the hydrolysis is carried out in a temperature rangefrom 140° C. to 180° C.
 19. The process according to claim 16 wherein acarboxylic acid is formed in the hydrolysis, and at least a portionthereof is removed from the reaction solution during the reaction oronce the reaction is complete.
 20. The process according to claim 16wherein once the reaction is complete, the methionine is separated offin the form of a solid, and the filtrate is recycled.